Cytotoxic substituted indolizines as new colchicine site tubulin polymerisation inhibitors

Abstract

A potential microtubule destabilising series of new indolizine derivatives was synthesised and tested for their anticancer activity against a panel of 60 human cancer cell lines. Compounds 11a, 11b, 15a, and 15j showed a broad spectrum of growth inhibitory activity against cancer cell lines representing leukaemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast, and prostate. Among them, compound 11a was distinguishable by its excellent cytostatic activity, showing GI₅₀ values in the range of 10–100 nM on 43 cell lines. The less potent compounds 15a and 15j in terms of GI₅₀ values showed a high cytotoxic effect against tested colon cancer, CNS cancer, renal cancer and melanoma cell lines and only on few cell lines from other types of cancer. In vitro assaying revealed tubulin polymerisation inhibition by all active compounds. Molecular docking showed good complementarity of active compounds with the colchicine binding site of tubulin.

Graphical Abstract

Keywords:

• Indolizine
• anticancer
• tubulin polymerisation inhibitors
• Phenstatin
• pyridyl

Acknowledgements

The authors acknowledge National Cancer Institute for the anticancer evaluation of the compounds on their 60-cell panel. The testing was performed by the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (the URL to the Program’s website: http://dtp.cancer.gov/). We thank CERNESIM Research Center from Alexandru Ioan Cuza University of Iasi for the NMR experiments.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Authors are thankful to Ministry of Research and Innovation within Program 1– Development of the national RD system, Subprogram 1.2 – Institutional Performance – RDI excellence funding projects, Contract no. 34PFE/19.10.2018 for financial support. The authors are also grateful for the financial support from the European Union’s Horizon 2020 research and innovation programme (grant agreement 667387).